Nonalcoholic fatty liver disease (NAFLD) is the fastest-growing cause of liver dysfunction, affecting more than 80 million Americans, and leading to nonalcoholic steatohepatitis (NASH) in nearly 10 million patients. The disease is a constellation of abnormal metabolism and liver histopathology, including: simple steatosis, steatohepatitis, cellular injury, and fibrosis. Its progressive form, NASH, is associated with hepatic fibrosis that can progress into cirrhosis. NAFLD is associated with obesity, metabolic syndrome and type 2 diabetes mellitus. Intrahepatic lipid accumulation is associated with increased lipolysis, VLDL-triglyceride secretion, and oxidative stress. CEACAM1, a transmembrane substrate of the insulin receptor, promotes hepatic insulin clearance and mediates a negative acute effect of insulin on fatty acid synthase activity, thus regulating insulin and lipid metabolism. NAFLD patients exhibit a marked reduction in their hepatic CEACAM1 levels, and the degree of the disease correlates with the extent of the loss of CEACAM1. Ceacam1 ablation in liver recapitulates faithfully all features of human NAFLD/NASH, including spontaneous chicken-wire fibrosis that is rarely observed in mice on C57BL/6 background. Activated hepatic stellate cells (HSC) is a major source of fibrosis. Because virtually all liver cells contribute to HSC activation, we set out to identify the main cellular sites for CEACAM1's regulation of fibrosis. Lipid accumulation in hepatocytes as well as excessive capillarization of the liver sinusoid can activate HSC. Preliminary data show: 1) reduced Ceacam1 mRNA in activated HSC from humans and CCl4-treated mice and 2) spontaneous hepatic fibrosis in AlbCre+Cc1fl/fl and VECad+Cc1fl/fl mice with liver-specific and endothelial cell-specific Ceacam1 deletion, respectively. Given the well-documented role of CEACAM1 in regulating lipid homeostasis in hepatocytes, and in maintaining vascular integrity, we hypothesized that CEACAM1 function along the stellate cell-endothelial cell axis is critical to the pathogenesis of hepatic fibrosis. To test this hypothesis, we propose in Aim 1 to examine the cell-autonomous metabolic and fibrogenic effect of deleting Ceacam1 from HSC to test whether CEACAM1's regulation of HSC activation and fibrosis is independent of its effect on insulin clearance and fatty acid synthesis in hepatocytes. In Aim 2, we will examine the cell non-autonomous effect of deleting Ceacam1 from endothelial cells on HSC activation. In Aim 3, we will investigate whether Ceacam1 induction mediates the therapeutic effect of PPAR? agonist, pioglitazone. The ultimate goal of this work is to identify CEACAM1-dependent pathways in the pathogenesis of fibrosis to develop appropriate therapeutic targets.